Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Kohat, Khyber Pakhtunkhwa, 26000, Pakistan.
Medical Research, RILD Wellcome Wolfson Centre (Level 4), Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UK.
BMC Neurol. 2024 Oct 16;24(1):394. doi: 10.1186/s12883-024-03882-y.
Hereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis.
Families from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen's h.
WES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies.
This study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.
遗传性运动感觉神经病（HMSN）是一组遗传性进行性周围神经病，其特征为慢性节段性脱髓鞘和/或轴突变性导致神经传导速度降低。HMSN 在临床和遗传上具有高度异质性，具有多种遗传模式，并与其他遗传性神经病和神经退行性疾病存在表型重叠。由于这种高度复杂性和遗传异质性，本研究旨在通过全外显子组测序（WES）进行变异鉴定，并通过 Sanger 测序进行验证和分离分析，以阐明巴基斯坦家族中 HMSN 的遗传原因，从而实现准确的临床诊断。
纳入来自开伯尔-普赫图赫瓦省（Khyber Pakhtunkhwa）的至少有两名成员表现出 HMSN 症状且此前未进行过遗传分析的家族。遗传研究的转介是基于当地神经科医生提示 HMSN 临床特征进行的。对每个家族的受累个体进行 WES，使用 Sanger 测序验证和分析家系成员中鉴定出的变异的分离。对受累个体的发病年龄进行评估，以评估其变异性，并使用比例差异和 Cohen's h 与现有文献比较遗传诊断的成功率。
WES 在 9 个家族中的 5 个中鉴定出 GDAP1（c.310 + 4 A > G，p.？）、SETX（c.5948_5949del，p.(Asn1984Profs*30)）、IGHMBP2（c.1591 C > A，p.(Pro531Thr)）和 NARS1（c.1633 C > T，p.(Arg545Cys）的纯合致病性变异，符合常染色体隐性遗传模式。此外，在 HMSN 家族中，SETX 变异导致小脑共济失调，而 NARS1 变异与智力障碍有关。根据美国医学遗传学与基因组学学院的标准，GDAP1 变异被归类为意义不明的变异，而 SETX 和 IGHMBP2 中的变异被归类为致病性，NARS1 变异被归类为可能致病性。发病年龄为 1 至 15 岁（均值=5.13，标准差=3.61），HMSN 家族中 55.56%实现了遗传诊断，与以往研究相比，效应量较小。
本研究扩展了巴基斯坦 HMSN 和 HMSN 加型神经病的分子遗传学谱，并促进了受累家庭的准确诊断、遗传咨询和临床管理。
